KR20010042210A - Preventives/remedies for urinary disorder - Google Patents

Abstract

The present invention is formula (I)

[Formula I]

[Wherein, Ring A represents phenyl substituted with hydroxy (lower alkyl); Ring B represents phenyl substituted with lower alkyl; Alk represents lower alkyl; R contains an optionally substituted nitrogen-containing aromatic heterocyclic monocyclic group or a pharmacologically acceptable salt thereof as an active ingredient, and exhibits an excellent inhibitory effect on the increase in urethral resistance caused by endothelin Provided are novel prophylactic / therapeutic agents useful for the prophylaxis and treatment of urinary disorders related to Tellin.

Description

Prevention and treatment of urination disorder {PREVENTIVES / REMEDIES FOR URINARY DISORDER}

Prostatic hyperplasia tends to increase year by year with an increase in the aging population, and as the prostate enlargement progresses, prostate urethral pressure increases thereby, and as a result, prostatic hyperplasia is accompanied by clinical symptoms such as urination disorder. . In recent treatment of urination disorders associated with prostatic hyperplasia, agents usually having prostatic urethral pressure-reducing activity, for example tamsulosin hydrochloride (chemical name: 5- [2-[[2- (ethoxyphenoxy) ethyl) [Alpha] 1 receptor antagonist, such as] amino] propyl] -2-methoxy-benzenesulfonamide hydrochloride).

Recently, various studies on the physiological action of endothelin on the prostate gland have been conducted. Entotelin-1, a peptide having a strong vasoconstrictive action, shows an activity of increasing prostate urethral pressure, and the activity of endothelin-1 It has been reported that it is not inhibited by the α1 receptor antagonist (see Journal of Urology, Vol. 158, page 253, 1997).

It has also been reported that cyclic peptide compounds of the formulas inhibit the contraction of smooth muscle of hypertrophic prostate tumors induced by endothelin-1 (Journal of Japanese Urology Society, Vol. 84, No. 9, pages 1649-1654). , 1993).

In addition, certain phenylacetic acid derivatives (ie, N- (4-isopropylbenzenesulfonyl) -α- (4-carboxy-2-n-propylphenoxy) -3,4-methylene-dioxyphenylacetamide dipotassium It has been suggested that the salt) exhibits the activity of inhibiting the prostate contraction caused by endothelin-1, and thus the phenoxyphenylacetic acid compound can be used for the treatment of urination disorders associated with enlarged prostate (JP- A-8-508034).

On the other hand, the benzenesulfonamide derivatives of formula I, the active ingredient of the present invention, exhibit excellent endothelin receptor antagonism, and can be used for circulatory diseases such as hypertension, pulmonary hypertension, renal hypertension, Raynaud's disease, myocardial infarction, and atherosclerosis. While it is known to be useful for treatment (JP-A-9-59160), it has not been reported that the compound exhibits activity to ameliorate urination disorders associated with prostatic hyperplasia.

Disclosure of the Invention

It is an object of the present invention to provide a novel prophylactic or therapeutic agent for urination disorders comprising a benzenesulfonamide derivative as an active ingredient.

As a result of intensive studies, the present inventors have found that some kinds of benzenesulfonamide derivatives effectively suppress an increase in prostate urethral pressure caused by endothelin-1, and have completed the present invention.

That is, the present invention relates to a prophylactic or therapeutic agent for urination disorders containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient

In the above formula,

Ring A is a hydroxy lower alkyl substituted phenyl group;

Ring B is a lower alkyl substituted phenyl group;

Alk is a lower alkylene group;

R is a 6-membered substituted or unsubstituted nitrogen-containing aromatic heteromonocyclic group.

Best Mode for Carrying Out the Invention

In the benzenesulfonamide derivative of the formula (I) which is the active ingredient of the present invention, the six-membered nitrogen-containing aromatic heteromonocyclic group is, for example, a pyridyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group and the like. The substituent of the aromatic heterocyclic group is, for example, a halogen atom (for example, bromine atom, chlorine atom, fluorine atom) and the like.

Examples of the active ingredient of the above formula (I) of the present invention include ring A is a hydroxy-C _1-6 alkyl substituted phenyl group, ring B is a C _1-6 alkyl substituted phenyl group; Alk is a C _1-6 alkylene group and R is a six-membered nitrogen-containing aromatic heteromonocyclic group (e.g. pyrimidinyl group, etc.) which may be optionally substituted by halogen atoms (e.g. bromine atoms, etc.) There is a compound of formula (I).

Preferred among the active ingredients, for example, ring A is a hydroxy-C _1-4 alkyl substituted phenyl group (for example, 2-hydroxy-1,1-dimethylethylphenyl group), Alk is an ethylene group, and a ring There is a compound of formula I, wherein B is a C _1-4 alkyl substituted phenyl group (eg methylphenyl group) and R is a bromopyrimidinyl group.

Of these, particularly preferred compounds are 4- (2-hydroxy-1,1-dimethylethyl) -N- [6- {2- (5-bromopyrimidin-2-yl-oxy) ethoxy} -5 -(4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide or a pharmaceutically acceptable salt thereof (eg an alkali metal salt, eg sodium salt).

Benzenesulfonamide derivatives of formula (I) which are the active ingredient of the present invention can be used in clinically free form or in the form of a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts may be acid addition salts with inorganic or organic acids, or salts with inorganic bases, organic bases or amino acids, for example hydrochloride, sulfate, hydrobromide, methanesulfonate, acetate, fumarate, male Salts with ates, oxalates, alkali metal salts (eg sodium salts, potassium salts, etc.), alkaline earth metal salts (eg magnesium salts, calcium salts, etc.), triethylamine salts, and lysine.

In addition, the benzenesulfonamide derivatives of formula (I) or their pharmaceutically acceptable salts, which are the active ingredients of the present invention, may include internal salts, adducts, complexes, hydrates and solvates thereof.

Benzenesulfonamide derivatives of formula (I) or their pharmaceutically acceptable salts, which are the active ingredients of the present invention, may be administered orally or parenterally and may be used in combination with pharmaceutically acceptable carriers or diluents, for example in pharmaceutical preparations such as tablets. Or in the form of injections.

Dosage forms for oral administration may be solid preparations such as tablets, granules, capsules, powders, or liquid preparations such as solution preparations and suspension preparations. Pharmaceutically acceptable carriers or diluents for oral preparations are conventional, e.g. binders (e.g. syrup, acacia rubber, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, etc.), excipients (e.g. Lactose, white sugar, corn starch, potassium phosphate, sorbitol, glycine, etc., lubricants (e.g. magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (e.g. potato starch, etc.), and wetting agents ( For example sodium laurylsulfate, and the like.

On the other hand, dosage forms for parenteral administration are preferably drip infusion preparations or injection preparations using distilled water, saline or aqueous glucose solution for injection.

Dosages of the benzenesulfonamide derivatives of formula (I) or their pharmaceutically acceptable salts, which are the active ingredients of the present invention, may vary depending on the route of administration, the age, weight or condition of the patient, or the severity of the disease to be treated, but the daily dosage thereof Is generally in the range of about 0.01 mg to 100 mg, preferably in the range of 0.01 mg to 10 mg.

Benzenesulfonamide derivatives of formula (I) or their pharmaceutically acceptable salts, which are the active ingredients of the present invention, exhibit excellent inhibitory activity against increases in urethral resistance caused by endothelin, and the urination disorder caused by endothelin ( Useful for preventing or treating urination disorders associated with, for example, prostatic hyperplasia.

For example, as shown in Experiment 1 below, 4- (2-hydroxy-1,1-dimethylethyl) -N- [6- {2- (5-bromopyrimidin-2-yloxy) Toxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide sodium salt (1.5 hydrate) increased urethral resistance by intravenously administering endothelin-1 at a dose of 0.4 nmol / kg. In dogs, an intraduodenal administration at a dose of 1 mg / kg completely inhibited the increase in urethral resistance induced by endothelin-1.

According to the above results, benzenesulfonamide derivatives of formula I or pharmaceutically acceptable salts thereof, such as the compounds, are useful for the treatment of urination disorder caused by endothelin-1.

Benzenesulfonamide derivatives of the formula (I) or their pharmaceutically acceptable salts, which are the active ingredients of the invention, are for example acid acceptors (eg, according to the conventional methods disclosed in JP-A-9-59160). Alkali metal hydrides, alkali metal carbonates, alkali metal hydroxides, etc.),

[In the formula,

Ring A ₁ is a lower alkyl substituted phenyl group, wherein the lower alkyl group is substituted by a protective hydroxy group;

Other symbols are as defined above]

Or a salt thereof (e.g., a salt with an inorganic acid such as hydrochloride, sulfate, alkali metal salt (e.g. sodium salt), alkaline earth metal salt (e.g. calcium salt, etc.)),

X ¹ -R

[Wherein X ¹ is a reactive moiety and R is as defined above]

React with a compound of and remove the protecting group (common protecting group of a hydroxy group such as, for example, tetrahydropyranyl group, etc.) from the protective hydroxy group on Ring A _{1 in} a conventional manner, and then, if necessary, the product is pharmaceutically acceptable It can be prepared by converting to a salt.

In X ¹ of the compound of formula III, the reactive moiety is, for example, a halogen atom, for example a chlorine atom and the like.

The reaction of the compound of formula (II) or a salt thereof with the compound of formula (III) is carried out at room temperature to 150 ° C, preferably at room temperature to 100 ° C, in a suitable solvent (e.g. tetrahydrofuran, dimethylsulfoxide, dimethylformamide, etc.). Is performed.

Experiment

Inhibitory activity against increased urethral resistance induced by endothelin-1

Way:

Four male hybrid dogs (body weight: 10-14 kg) fasted overnight were inserted with a polyethylene tube in both femoral veins under pentobarbital anesthesia (30 mg / kg, i.v.). Anesthesia was maintained by continuous infusion of pentobarbital (4.5 mg / kg) from the polyethylene tube and the dog was vented with an animal inhaler (20 strokes per minute, 15 ml / kg / aeration). A polyethylene tube for administering the test compound was then inserted into the duodenum and the bladder and urethral bases were exposed. In order to prevent urine from backing up in the bladder, a polyethylene tube holding a silicone tube was inserted into both ureters to secure an extracorporeal discharge path of urine. In addition, in order to measure the prostate urethral resistance of the ventral part and the ventral part, the bladder government was dissected and a two-hole open-tip catheter (12 Fr, manufactured by Cliny) was inserted into the prostate urethra through the bladder part. After the catheter was connected at the urethral base and the bladder part, one end thereof was connected to a pressure transducer and a syringe pump (SP-25, manufactured by Terumo Corporation) via a three-way turncock. Subsequently, a change in the perfusion pressure (ie, a change in urethral resistance, in mmHg) generated by continuous infusion (3 ml / hour) of physiological saline (37 ° C.) through the catheter was obtained by using a carrier amplifier (AP-621G, Nihon Kohden). Corporation), and recorded on a linear coder (linearcorder, WR-3701, manufactured by Graphtec Corporation).

In order to increase urethral resistance, a physiological saline solution of phenylephrine (α1 agonist) or endothelin-1 was administered intravenously to a dog at a time not less than 60 minutes after the operation (dose: 0.1 ml / kg )

As the test compound, 4- (2-hydroxy-1,1-dimethylethyl) -N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (4 -Methylphenyl) -pyrimidin-4-yl] benzenesulfonamide sodium salt 1.5 hydrate was used (the compound was dissolved in 5% hydroxypropyl-β-cyclic dextrin and then administered).

result:

As shown in Table 1 below, phenylephrine (intravenous administration) increased anesthetically prostate urethral resistance in anesthesia dogs at a dose of 0.3 μg / kg or more, and increased 30 μg / kg of phenylephrine. The mean increase in prostate urethral resistance when administered was 4.9 mmHg.

On the other hand, as shown in Table 2, endothelin-1 (intravenous administration), at a dose of 0.05 nmol / kg or more, was shown to increase the prostate urethral resistance activity depending on the dose, 0.4 to 0.8 The maximum prostate urethral resistance increase was shown at the dose of nmol / kg. The activity of endothelin-1 acted longer than that of phenylephrine. The average increase in urethral resistance with endothelin-1 0.4 nmol / kg was 18.9 mmHg, which was about 4 times greater than the average for 30 μg / kg phenylephrine.

In addition, the test compound (1 mg / kg, duodenal administration) completely inhibited the increase in urethral resistance by endothelin-1 administration (dose of 0.4 nmol / kg). From the above results, it can be seen that the benzenesulfonamide derivatives of the formula (I) of the present invention or pharmaceutically acceptable salts thereof are useful for the treatment of urination disorders associated with enlarged prostate.

Urine Resistance Increasing Activity of Phenylephrine in Anesthetized Dogs Dose (μg / kg) 0.3 One 3 10 30 Urinary Pressure (mmHg) 0.8 2.1 3.3 4.6 4.9

Increasing Activity of Urethral Resistance of Endothelin-1 in Anesthetized Dogs Dose (nmol / kg) 0.05 0.1 0.2 0.4 0.8 Urinary Pressure (mmHg) 2.2 4.5 14.3 18.9 15.4

Produce

(1) To 1.3 liters of ethylene glycol was slowly added sodium (35.65 g) at 23 to 75 ° C., to which N- [6-chloro-5- (4-methylphenyl) pyrimidin-4-yl] -4- [ 2- (2-tetrahydropyranyloxy) -1,1-dimethylethyl] benzenesulfonamide (160 g) was added at 4 ° C. The mixture was stirred at 100 ° C. for 16 h and allowed to cool to rt. Under ice-cooling, the reaction mixture was poured into a mixture of saturated aqueous ammonium chloride solution and ethyl acetate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and the organic layer was dried over anhydrous sodium sulfate and activated carbon. The solid material was filtered off through a pad of celite and the filtrate was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give N- [6- (2-hydroxyethoxy) -5- (4-methylphenyl) -pyrimidin-4-yl] -4- [2- ( 2- (tetrahydropyranyloxy) -1,1-dimethyl-ethyl] benzenesulfonamide (80.26 g) was obtained as colorless crystals, and the mother liquor was concentrated and the product was recrystallized from ethyl acetate-diisopropyl ether. 73.1 g of crystals of the above compound were obtained.

Melting Point: 137.0-138.0 ℃

(2) 80.0 g of the product obtained in (1) above are dissolved in a mixture of 330 ml of tetrahydrofuran and 132 ml of dimethylacetamide and sodium hydride (60% oily dispersion, 17.72 g) in 330 ml of tetrahydrofuran under ice cooling. To the suspension was added dropwise. At the same temperature, 5-bromo-2-chloro-pyrimidine (40.0 g, Australian Jouurnal of Chemistry, Vol. 17, page 794, 1964) was added to the mixture and the mixture was stirred for 16 hours at room temperature. The reaction mixture was poured into a mixture of ice and saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and treated with activated carbon. The product was filtered through a pad of celite to remove solid material. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; chloroform: ethyl acetate = 30: 1 to 20: 1), crystallized from ethyl acetate-diisopropyl ether to give N- [ 6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] -4- [2- (2-tetrahydropyranyloxy 91.83 g of) -1,1-dimethylethyl] -benzenesulfonamide was obtained as colorless crystals.

Melting Point: 138.0-139.0 ℃

(3) A mixture of the product (120 g), p-toluenesulfonic acid monohydrate (39.21 g) and tetrahydrofuran (950 ml), 190 ml of methanol and 95 ml of water obtained in (2) was mixed and the mixture was Stir at room temperature for 17 hours. The reaction mixture thus obtained was further stirred for 3 hours while maintaining at 40 to 60 ° C. The reaction mixture is cooled to room temperature and 26.16 g of p-toluenesulfonic acid monohydrate is added thereto at room temperature. The mixture was stirred at room temperature for 2 hours and refluxed for 15 minutes by adding 250 ml of methanol. The reaction mixture was cooled to room temperature, to which an aqueous solution of sodium hydrogen carbonate (29.58 g) was added, and the mixture was concentrated under reduced pressure. Diisopropyl ether and water were added to the resulting residue, and the precipitated crystals were collected by filtration, dissolved in a mixture of chloroform and tetrahydrofuran, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol, cooled and the precipitated crystals were collected by filtration to give 4- (2-hydroxy-1,1-dimethylethyl) -N- [6- {2- (5-bromopyrimidine 67.67 g of 2-yloxy) ethoxy} -5- (4-methylphenyl) -pyrimidin-4-yl] benzenesulfonamide were obtained as colorless crystals.

Melting Point: 181.0-182.0 ℃

(4) A mixture of 28% sodium methoxide (32.3 g) and methanol (200 ml) in methanol in a suspension of the product (107.0 g) obtained in (3) above in a mixture of 1000 ml tetrahydrofuran and 200 ml methanol. Was added dropwise over 2 hours in a dry ice-acetone bath. The mixture was concentrated at 35 ° C. under reduced pressure and methanol was added to the residue. The mixture was refluxed and the resulting solution was concentrated under reduced pressure to allow crystals to precipitate. The solution was stirred at rt for 16 h and the precipitated crystals were collected by filtration. The resulting crystals were dried at 70 ° C. under reduced pressure to afford 4- (2-hydroxy-1,1-dimethylethyl) -N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy } -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide sodium salt (70.7 g) was obtained (melting point: 218-234 ° C. (decomposition)). The product thus obtained was then dried under reduced pressure at 75-80 ° C. for 4.5 days and left overnight at atmospheric pressure, room temperature to afford 4- (2-hydroxy-1,1-dimethylethyl) -N- [6- { 2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide sodium salt 1.5 hydrate (70.74 g) was obtained as colorless crystals.

Melting Point: 202-243 ℃ (Decomposition)

Moisture Content (Karl Fischer Method): 4.34%

Reference Example 1

At 5 to 20 ° C., fumigated sulfuric acid is added dropwise to a solution of (2-acetoxy-1,1-dimethylethyl) benzene in methylene chloride (Journal of Organic Chemistry, Vol. 23, p. 920, 1958), followed by Onyl chloride was further added at 10-12 ° C. and the mixture was stirred at rt for 18 h. The reaction mixture was poured into iced water, to which ethyl acetate was added. Methylene chloride was distilled off and ethyl acetate was added to the residue. The mixture was extracted with ethyl acetate and the organic layer was washed with aqueous sodium chloride solution. Aqueous ammonia was added dropwise to the organic layer at 10-18 ° C. and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was acidified with concentrated hydrochloric acid and the precipitated crystals were collected by filtration, washed with water and concentrated under reduced pressure. The residue was crystallized from chloroform to give crystals of 4- (2-acetoxy-1,1-dimethylethyl) benzenesulfonamide.

Melting point: 156-158 deg.

Reference Example 2

(1) 4,6-dichloro-5- (4-methylphenyl) pyrimidine (10.0 g), 4- (2-acetoxy-1,1-dimethylethyl) benzenesulfonamide (11.58 g), potassium carbonate (14.45 g) and 50 ml of dimethylsulfoxide were stirred at 75 ° C. (bulk temperature) for 3 hours, to which 0.34 g of 4- (2-acetoxy-1,1-dimethylethyl) benzenesulfonamide was further added. . The mixture was stirred at 70-75 ° C. for 1.5 h, the reaction mixture was cooled and poured into a mixture of ice (100 g) and concentrated hydrochloric acid (60 ml). The mixture was extracted with ethyl acetate and the organic layer was washed, dried and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to give 4- (2-acetoxy-1,1-dimethylethyl) -N- {6-chloro-5- (4-methylphenyl) pyrimidine-4- 14.97 g of benzenesulfonamide was obtained as a colorless needle.

Melting point: 188.0-189.0 ° C.

(2) The product (20.0 g) obtained in (1) was suspended in a mixture of tetrahydrofuran (60 ml) and methanol (60 ml), and 4N aqueous sodium hydroxide solution (52.8 ml) was added dropwise in an ice-water bath. It was. The mixture was stirred at the same temperature for 1 hour, neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was washed, dried and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was concentrated under atmospheric pressure. The concentrate was diluted with n-hexane and left at room temperature. The precipitated crystals were collected by filtration and washed to give N- {6-chloro-5- (4-methylphenyl) pyrimidin-4-yl} -4- (2-hydroxy-1,1-dimethylethyl) benzenesulphone Amide (17.31 g) was obtained as a colorless needle.

Melting point: 227-228 deg.

(3) At room temperature, dihydropyran (39 ml) and camphor-sulfonic acid (1.54 g) are added to a suspension of the product (142.89 g) obtained in (2) above in methylene chloride, and the mixture is stirred at the same temperature. Stir for 30 minutes. A saturated aqueous sodium hydrogen carbonate solution (9 ml) was added to the reaction mixture, and the solvent was distilled off. Ethyl acetate (2 liters) was added to the residue, and the precipitated crystals were collected by filtration and washed with water. The ethyl acetate layer was washed, dried and concentrated under reduced pressure. The residue and crystals obtained above were combined, dissolved in a mixture of chloroform and tetrahydrofuran, dried and concentrated under reduced pressure. The residue was crystallized from a mixture of chloroform and diisopropyl ether to give N- [6-chloro-5- (4-methylphenyl) -pyrimidin-4-yl] -4- [2- (2-tetrahydropyranyloxy ) -1,1-dimethylethyl] benzenesulfonamide (158.59 g) was obtained as colorless crystals.

Melting point: 141.0-143.5 ° C.

The present invention relates to a novel prophylactic or therapeutic agent for urination disorders, and more particularly, to a prophylactic or therapeutic agent for urination disorders containing a benzenesulfonamide derivative of the formula (I) as an active ingredient.

The prophylactic or therapeutic agent for the urination disorder of the present invention exhibits excellent inhibitory activity against the increase in urethral resistance induced by endothelin, and thus is useful for the prevention or treatment of the urination disorder caused by endothelin.

Claims (15)

A prophylactic or therapeutic agent for urination disorders, which comprises as an active ingredient a compound of formula (I), or a pharmaceutically acceptable salt thereof: [Formula I] In the above formula, Ring A is a hydroxy lower alkyl substituted phenyl group; Ring B is a lower alkyl substituted phenyl group; Alk is a lower alkylene group; R is a 6-membered substituted or unsubstituted nitrogen-containing aromatic heteromonocyclic group. The agent for preventing or treating urination disorder according to claim 1, wherein R is a six-membered nitrogen-containing aromatic heteromonocyclic group substituted with a halogen atom. The agent for preventing or treating urination disorders according to claim 1 or 2, wherein the six-membered nitrogen-containing aromatic heteromonocyclic group is a pyrimidinyl group. The compound of claim 3, wherein ring A is a hydroxy-C _1-4 alkyl substituted phenyl group, and ring B is a C _1-4 alkyl substituted phenyl group; An agent for preventing or treating urination disorder, characterized in that Alk is an ethylene group and R is a pyrimidinyl group substituted by a bromine atom as an active ingredient. 4- (2-hydroxy-1,1-dimethylethyl) -N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy} -5- (4-methylphenyl) pyrimidine 4-yl] benzenesulfonamide or a pharmaceutically acceptable salt thereof as an active ingredient, preventing or treating urination disorder. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a prophylactic or therapeutic agent for urination disorders: [Formula I] In the above formula, Ring A is a hydroxy lower alkyl substituted phenyl group; Ring B is a lower alkyl substituted phenyl group; Alk is a lower alkylene group; R is a 6-membered substituted or unsubstituted nitrogen-containing aromatic heteromonocyclic group. 7. Use according to claim 6, wherein R is a six-membered nitrogen-containing aromatic heteromonocyclic group substituted with a halogen atom. Use according to claim 6 or 7, wherein the six-membered nitrogen-containing aromatic heteromonocyclic group is a pyrimidinyl group. The compound of claim 6, wherein in Formula I, Ring A is a hydroxy-C _1-4 alkyl substituted phenyl group, Ring B is a C _1-4 alkyl substituted phenyl group; Alk is an ethylene group, and R is a pyrimidinyl group substituted by a bromine atom. The compound of formula I, wherein the compound of formula I is 4- (2-hydroxy-1,1-dimethylethyl) -N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy } -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide. A method of preventing or treating a urination disorder, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient suffering from or likely to have a urination disorder: [Formula I] In the above formula, Ring A is a hydroxy lower alkyl substituted phenyl group; Ring B is a lower alkyl substituted phenyl group; Alk is a lower alkylene group; R is a 6-membered substituted or unsubstituted nitrogen-containing aromatic heteromonocyclic group. 12. The method for preventing or treating urination disorder according to claim 11, wherein R is a six-membered nitrogen-containing aromatic heteromonocyclic group substituted with a halogen atom. The method for preventing or treating urination disorder according to claim 11 or 12, wherein the six-membered nitrogen-containing aromatic heteromonocyclic group is a pyrimidinyl group. The compound of claim 11, wherein in Formula I, Ring A is a hydroxy-C _1-4 alkyl substituted phenyl group, Ring B is a C _1-4 alkyl substituted phenyl group; Alk is an ethylene group, R is a pyrimidinyl group substituted by a bromine atom, The prevention or treatment method of the urination disorder characterized by the above-mentioned. 12. The compound of formula 11, wherein the compound of formula I is 4- (2-hydroxy-1,1-dimethylethyl) -N- [6- {2- (5-bromopyrimidin-2-yloxy) ethoxy } -5- (4-methylphenyl) pyrimidin-4-yl] benzenesulfonamide. The method of preventing or treating urination disorder.